Submissions for variant NM_007194.4(CHEK2):c.1259+1G>A

dbSNP: rs121908707

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587596	SCV000698758	likely pathogenic	Li-Fraumeni syndrome	2016-04-18	criteria provided, single submitter	clinical testing	Variant summary: The c.1259+1G>A variant involves the alteration of a conserved nucleotide resulting in an intronic change. This variant is located at a position that is widely known to affect splicing and 5/5 splicing prediction programs via Alamut predict the complete loss of a splicing donor site. The variant is absent from the large, broad ExAC control population and has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant has been classified as Likely Pathogenic until additional evidence becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860142	SCV002270417	likely pathogenic	Familial cancer of breast	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 30303537). ClinVar contains an entry for this variant (Variation ID: 496341). Studies have shown that disruption of this splice site results in skipping of exon 11 (also known as exon 10), and produces a non-functional protein and/or introduces a premature termination codon (PMID: 26506619). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002431744	SCV002681425	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-10-05	criteria provided, single submitter	clinical testing	The c.1259+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 10 of the CHEK2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV001860142	SCV004044818	likely pathogenic	Familial cancer of breast	2023-06-28	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.